This project is based upon the observation that disruption of the fibroblast growth factor receptor-2 (FGFR-2)-keratinocyte growth factor (KGF) axis in the lung produces profound abnormalities of branching morphogenesis and lung growth during fetal mouse development. Newborn transgenic mice expressing a dominant negative FGFR-2 (FGFR-2dn) in the primordial pulmonary epithelium display severe pulmonary hypoplasia while transgenic mice expressing high levels of KGF in the developing lung die in utero with massive airway dilatation and disordered alveolar formation. Studies in this project are based upon the hypothesis that the precise temporal/spatial regulation of KGF expression is required for successful lung development and repair following oxygen injury. Localization of KGF expression within the lung will be determined in the fetal, neonatal and adult mouse using in situ hybridization. In vitro and in vivo models are used to establish the mechanisms controlling specific pulmonary KGF mRNA expression. Epigenetic controls of KGF expression will be determined using in vitro cell culture models, transient transfection assays, and transgenic mouse models. The physical structure of the murine KGF locus will be determined in order to identify the cis and trans active factors that mediate KGF expression in the lung. Mechanisms of modulation of KGF expression following oxygen injury in the newborn and adult animal will be identified. Transgenic mice expressing a chimeric tetracycline transactivator under the control of the SP-C promoter will be used to temporally control the expression of KGF or FGFR-2dn in the lung, thus modulating the KGF/FGFR-2 axis throughout development. Morphometric and physiologic studies will complement an analysis of lung structure and cellular composition in the context of transgene induction. These studies will define the location and basis for expression of KGF in the lung and determine the consequences, detrimental and beneficial, associated with aberrant KGF expression during development and injury. Correlation with human disease states likely to be associated with aberrant KGF expression such as cystadenomatoid malformation and bronchopulmonary dysplasia will promote understanding of their pathogenesis and opportunities for novel therapeutic approaches.